DESCRIPTION (Adapted from the application): The polyketide drugs FK506 or Rapamycin bind to the protein FKBP-12 and then to the effector proteins calcineurin or RAFT-1 respectively to form ternary complexes. These FKBP-12 -polyketide-effector complexes are required for the immunosuppressive activities of FK506. Secondly, FK506 and Rapamycin can promote neurite outgrowth; however, this potential therapeutic function is not correlated to the binding to the effector proteins. Recently, studies have suggested that immunosuppressive and neurite outgrowth activities can be separated. It appears the neuroregenerative activity is retained by agents that bind to FKBP-12 but not to the effector proteins. It is the objective of this STTR proposal to design and prepare FKBP-12 binding analogs of FK506 and Rapamycin. The design will be based upon a computer-aided approach which will identify molecules with ground state conformation(s) complementary to the FKBP-12 binding domain but not complementary to effector domains. The optimal FKBP-12 binders identified virtually will be made by changing the corresponding segments of the polyketide synthase coding genes. The analogs made will be tested through binding and cell culture assays. It is the specific aim of this STTR to: 1) Discover neuroregenerative analogs of Rapamycin and FK506 by computer-aided search 2) Generate analogs by manipulation of PKS gene clusters and test them by binding and cell culture assays. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE